Aging and immunity to infections. Infectious disease results in high morbidity and mortality in the elderly and current vaccines are often ineffective. Defining the underlying nature of the defects is extremely difficult in man because the population is genetically diverse, requiring large numbers of subjects and cannot be readily manipulated. Mouse models allow us to determine precisely whether individual subsets of cells are impaired, what mechanisms are compromised and how defects might be reversed. Such models have identified a profound, age-related defect in CD4 T cells which reduces primary effector generation, memory generation and antibody production. We plan to study the impact of aging on responses of CD4 and CD8 T cells to viruses. We will determine which responses are compromised by aging, what mechanisms are responsible for the defects, and whether adjuvants or cytokines can enhance responses and/or overcome the known defects. These studies will generate important information that should elucidate immune defects that arise in T cells with aging and contribute in the future to the development of strategies to effectively vaccinate the elderly. The Program comprises 4 Projects: 1. Aging and CD4 Immunity to Influenza Virus, will determine how aging impacts the in vivo response of naive CD4 T cells, whether adjuvants can rescue the responses of aged naive CD4 T cells and what potential mechanisms are involved in overcoming their poor responsiveness. 2. Enhancing aged CD4 cognate function with cytokines, will determine the impact of aged CD4 T cell defects on their ability to provide cognate help for B cells and hence on Ab production and it will determine if proinflammatroy cytokines can improve the in vivo function of aged CD4 T cells responding to protein antigens. 3. Impact of Aging on CD8 Memory T Cell Subsets, will study the impact of age on memory CD8 T cells, including the distribution and turnover of distinct memory subsets, their functional characteristics, and the stability of vaccine-induced CD8 memory populations. 4. Impact of Aging on Immune Control of a Persistent Virus will determine the impact of aging on cellular and humoral immunity to a latent murine y-herpesvirus, and the consequences for immune control of the virus in aged individuals.